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Elife March 28, 2016; 5
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Stochasticity in the miR-9/Hes1 oscillatory network can account for clonal heterogeneity in the timing of differentiation.

Phillips NE , Manning CS , Pettini T , Biga V , Marinopoulou E , Stanley P , Boyd J , Bagnall J , Paszek P , Spiller DG , White MR , Goodfellow M , Galla T , Rattray M , Papalopulu N .

Recent studies suggest that cells make stochastic choices with respect to differentiation or division. However, the molecular mechanism underlying such stochasticity is unknown. We previously proposed that the timing of vertebrate neuronal differentiation is regulated by molecular oscillations of a transcriptional repressor, HES1, tuned by a post-transcriptional repressor, miR-9. Here, we computationally model the effects of intrinsic noise on the Hes1/miR-9 oscillator as a consequence of low molecular numbers of interacting species, determined experimentally. We report that increased stochasticity spreads the timing of differentiation in a population, such that initially equivalent cells differentiate over a period of time. Surprisingly, inherent stochasticity also increases the robustness of the progenitor state and lessens the impact of unequal, random distribution of molecules at cell division on the temporal spread of differentiation at the population level. This advantageous use of biological noise contrasts with the view that noise needs to be counteracted.

PubMed ID: 27700985
PMC ID: PMC5050025
Article link: Elife
Grant support: [+]

Species referenced: Xenopus
Genes referenced: gnl3 hes1 kit lmnb1 mapt ubc

Article Images: [+] show captions
References [+] :
Aggarwal, Concentration Sensing by the Moving Nucleus in Cell Fate Determination: A Computational Analysis. 2016, Pubmed